1. Field of the Invention
The present invention relates to a novel method of administering therapeutic agents including antihistamines and anti-nausea and anti-emetic agents and to novel dosage forms containing such agents adapted for nasal administration.
The invention provides a novel method of administering therapeutic agents that are antihistaminic or inhibit nausea and emesis in mammals. Nausea and emesis are often induced by stimulation of either the chemoreceptor trigger zone or the emesis (or vomiting) center in the central nervous system. Such stimulation can be caused by afferent stimulation (e.g., tactile pharyngeal impulses, labrynthine disturbances, motion, increased intracranial pressure, pain, distention of viscera or psychologic factors) or blood born emetic substances (e.g., as seen during pregnancy, cancer chemotherapy, uremia, radiation therapy, electrolyte and endocrine disturbances, or the presence of chemical emetic substances).
The invention further provides dosage forms of those agents which are adapted for nasal administration and which include solutions, suspensions, sustained release formulations, gels and ointments. The therapeutic agents include selected antihistamines including those with antitussive, anticholenergic, antipruritic, sedative and antianxiety properties, as well as selected antinausea and antiemetic agents.
2. Background Art
A number of antihistaminic, antinausea and antiemetic agents are known. Such agents are widely used therapeutically, chiefly in the treatment of vertigo, motion-sickness, hypersensitivity phenomena (anaphylaxis and allergy), rhinitis, sinusitis and gastroesophageal reflux diseases. Unfortunately, many of these agents when used: [1] cause undesirable side effects, [2] are inefficiently and variably absorbed from current dosage forms, [3] are difficult or inconvenient to administer in the current dosage forms after the onset of emesis or nausea, and [4] have delayed onset of pharmacological activity when administered by current dosage forms. It has now been unexpectedly discovered that these pharmacologically active agents can be administered by nasal delivery to provide: enhanced bioavailability, minimized variations in blood levels, more rapid onset of activity and reduced dosages when compared to most current methods of administration (e.g., oral, subcutaneous, intra-muscular or by way of suppository).
Nasal delivery of therapeutic agents has been well known for a number of years. See, for example, U.S. Pat. Nos. 4,428,883; 4,284,648 and 4,394,390; and PCT application International Publication Number WO83/00286. See also, Hussain et al, J. Pharm. Sci.: 68, No. 8, 2196 (1979); 69 1240 (1980) and 69 1411 (1980).
The PCT document describes nasal compositions for the administration of scopalamine, a parasympathetic blocking agent but fails to teach or recognize that a therapeutic response can be elicited at a dosage level which is only a fraction of that normally employed.
While nasal administration of certain therapeutic agents to mammals, especially humans is known, it is not a necessary conclusion from such knowledge that all therapeutic agents can be usefully administered by this route. In fact it has been shown that many drugs cannot be usefully administered by the nasal route. It certainly is not a suggestion that the compounds of this invention can be usefully administered nasally to achieve enhanced bioavailability and sustained therapeutic blood levels.
Zatuchinin, et al, for example reported in LHRH Peptides as Female and Male Contraceptives, Harper & Row, Publishers (1976) that, although LHRH peptides were effective when administered intranasally, a much higher dose was required than with parenteral administration.
Childrey and Essex reported an immediate and marked pressor response upon injection of 1 mg of nicotine in dogs, but little or no effect on injections of the same or larger amounts into the sinus of dogs or cats. Arch. Otolaryngol., 14 564 (1931).
Hussain et al have concluded that peptides are poorly absorbed through the nasal mucosa. See Transnasal Systemic Medications, Edited by Y. W. Chien, Elsevier Science Publishers, 1985, page 121 et seq, at page 122.
Physicians routinely utilize steriods such as flunisolide for topical treatment of nasal polyps because they are not rapidly absorbed and manifest excellent topical antiinflammatory with minimal systemic activity